Bis-basic compounds with tryptase-inhibitory activity

ABSTRACT

Compounds of which the following are exemplary:                    
     These have tryptase-inhibiting activity and are useful for the treatment of inflammatory and allergic disease conditions.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Serial No. 60/167,774, filed onNov. 29, 1999 is hereby claimed.

FIELD OF THE INVENTION

The present invention relates to bis-basic compounds havingtryptase-inhibiting activity, processes for preparing such compounds,their therapeutic use in the treatment of disease, and pharmaceuticalcompositions comprising such compounds.

SUMMARY OF THE INVENTION

Tryptase inhibitors may be used in the production of pharmaceuticalcompositions which are used to prevent and/or treat inflammatory and/orallergic conditions.

The object of the present invention is therefore to provide newcompounds that have a tryptase-inhibiting activity and may be used toprevent and treat conditions in which tryptase inhibitors may have atherapeutic value.

DETAILED DESCRIPTION OF THE INVENTION

The compounds according to the invention are bis-basic compounds ofgeneral formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NR^(1′)H,—CH₂NH₂, —CH₂CH₂NH₂ or —NH—C(═NH)—NH₂;

R¹ and R^(1′) which may be identical or different denote hydrogen, OH,—COR² or —COOR²;

R² denotes hydrogen, C₁-C₁₈-alkyl, aryl or aryl-C₁-C₆-alkyl;

Ar¹, Ar², Ar³, Ar⁴ and aryl which may be identical or different denoteC₆-C₁₀-aryl, which may optionally be mono- to tetrasubstituted by one ormore groups selected from among C₃-C₁₀-cycloalkyl, F, Cl , Br, I, OH,OR³, SR³, NR³R⁴, COOR³, C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl,whilst in the substituents C₁-C₆-alkyl and C₂-C₆-alkenyl one or morehydrogen atoms may optionally be replaced by F or OR³, or

 a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to threecarbon atoms may be replaced by one or more heteroatoms selected fromamong oxygen, nitrogen and sulphur and which may optionally be mono- totetrasubstituted by one or more groups selected from amongC₁-C₁₀-cycloalkyl, F, Cl, Br, I, OH, OR³, SR³, NR³R⁴, COOR³,C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, whilst in the substituentsC₁-C₆-alkyl and C₂-C₆-alkenyl one or more hydrogen atoms may optionallybe replaced by F or OR³;

R³ and R⁴ which may be identical or different denote hydrogen or a groupselected from among C₁-C₆-alkyl and C₃-C₆-cycloalkyl wherein one or morehydrogen atoms may optionally be replaced by F;

X¹, X², X³ and X⁴ which may be identical or different denote a bridgeselected from among —(CH₂)_(n)—, —(CH₂)_(n)O—, —(CH₂)_(n)—S—,—(CH₂)_(n)NR³— and —(CH₂)_(n)N⁺R³R⁴— where n=1 or 2;

A denotes a group selected from among C₂-C₁₆-alkylene andC₂-C₁₆-alkenylene, wherein optionally one or more hydrogen atoms may bereplaced by one or more groups selected from among F, R³, OR³ and COOR³,or A denotes C₂-C₁₆-alkynylene, or

A denotes —(CH₂)_(l)—D—(CH₂)_(m)—, whilst in the alkylene groups—(CH₂)_(l)— and —(CH₂)_(m)— one or two hydrogen atoms may optionally bereplaced by C₁-C₆-alkyl and wherein

D denotes aryl or C₃-C₁₀-cycloalkyl wherein one or more hydrogen atomsmay optionally be replaced by one or more groups selected from among F,R³ and OR³ and l and m, which may be identical or different, denote 0,1, 2, 3 or 4,

or

D denotes —O—, —S— or —NR³— and l and m, which may be identical ordifferent, denote 2, 3 or 4;

or

A denotes —G¹—(CH₂)_(r)—G²—, if X² or X³ denote —(CH₂)_(n)—, A may alsodenote —E¹—(CH₂)_(r)—G¹— or —E¹—(CH₂)_(r)—E²—,

wherein

r denotes the number 0, 1, 2, 3, 4, 5 or 6,

G¹ and G² which may be identical or different denote a single bond orC₃-C₁₀-cycloalkyl, but if r=0 or r=1 G¹ and G² cannot simultaneouslyrepresent a single bond;

E¹ and E² which may be identical or different denoteC₃-C₁₀-aza-cycloalkyl which contains one or two nitrogen atoms, whereinat least one N-atom is bound to X² or X³=(CH₂)_(n),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Preferred compounds of general formula (I) are those wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NR^(1′)H,—CH₂NH₂, —CH₂CH₂NH₂ or —NH—C(═NH)—NH₂;

R¹ and R^(1′) which may be identical or different denote hydrogen, OH,—COR² or —COOR²;

R² denotes hydrogen, C₁-C₁₄-alkyl, aryl or aryl-C₁-C₆-alkyl;

Ar¹, Ar², Ar³, Ar⁴ and aryl which may be identical or different, denoteC₆-C₁₀-aryl which may optionally be mono- to tetrasubstituted by one ormore groups selected from among C₃-C₈-cycloalkyl, F, Cl, Br, I, OH, OR³,NR³R⁴, COOR₃, C₁-C₆-alkyl, C₂-C₆-alkenyl and C₂-C₆-alkynyl, whilst inthe substituents C₁-C₆-alkyl and C₂-C₆-alkenyl one or more hydrogenatoms may optionally be replaced by F, or

 a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to threecarbon atoms may be replaced by one or more heteroatoms selected fromamong oxygen, nitrogen and sulphur and which may optionally be mono- totetrasubstituted by one or more groups selected from among F, OR³, COOR³or C₁-C₆-alkyl, wherein in the substituent C₁-C₆-alkyl one or morehydrogen atoms may optionally be replaced by F;

R³ and R⁴ which may be identical or different denote hydrogen or a groupselected from among C₁-C₆-alkyl and C₃-C₆-cycloalkyl wherein one or morehydrogen atoms may optionally be replaced by F;

X¹, X², X³ and X⁴ which may be identical or different denote a bridgeselected from among —(CH₂)_(n)—, —(CH₂)_(n)O—, —(CH₂)_(n)—S—,—(CH₂)_(n)NR³— and —(CH₂)_(n)N⁺R³R⁴— where n=1 or 2;

A denotes a group selected from among C₂-C₁₄-alkylene andC₂-C₁₀-alkenylene, wherein optionally one or more hydrogen atoms may bereplaced by one or more groups selected from among F, R³, OR³ and COOR³,or A denotes C₂-C₁₀-alkynylene, or

A denotes —(CH₂)_(l)—D—(CH₂)_(m)—, whilst in the alkylene groups—(CH₂)_(l)— and —(CH₂)_(m)— one or two hydrogen atoms may optionally bereplaced by C₁-C₆-alkyl and wherein

D denotes aryl or C₃-C₈-cycloalkyl wherein one or more hydrogen atomsmay optionally be replaced by one or more groups selected from among F,R³ and OR³ and l and m, which may be identical or different, denote 0,1, 2, 3 or 4,

or

D denotes —O—, —S— or —NR³— and l and m, which may be identical ordifferent, denote 2, 3 or 4;

or

A denotes —G¹—(CH₂)_(r)—G²—,

if X² or X³ represents —(CH₂)_(n)—, A also denotes —E¹—(CH₂)_(r)—G¹— or—E¹—(CH₂)_(r)—E²—,

wherein

r denotes the number 0, 1, 2, 3, 4, 5 or 6,

G¹ and G² which may be identical or different denote a single bond orC₃-C₈-cycloalkyl, but if r=0 or r=1 G¹ and G² cannot simultaneouslyrepresent a single bond;

E¹ and E² which may be identical or different denoteC₃-C₈-aza-cycloalkyl which contains one or two nitrogen atoms, whereinat least one N-atom is bound to X² or X³=(CH₂)_(n),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Particularly preferred are compounds of general formula (I), wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NR^(1′)H,—CH₂NH₂, —CH₂CH₂NH₂ or —NH—C(═NH)—NH₂;

R¹ and R^(1′) which may be identical or different denote hydrogen, OH,—COR² or —COOR²;

R² denotes hydrogen, C₁-C₁₀-alkyl or aryl-C₁-C₄-alkyl;

Ar¹, Ar², Ar³, Ar⁴ and aryl which may be identical or different, denotephenyl or naphthyl which may optionally be mono-, di— or trisubstitutedby one or more groups selected from among F, OR³, NR³R⁴, COOR₃ orC₁-C₆-alkyl, wherein in the substituent C₁-C₆-alkyl one or more hydrogenatoms may optionally be replaced by F or OR³;

R³ and R⁴ which may be identical or different denote hydrogen or a groupselected from among cyclopropyl, cyclopentyl, cyclohexyl and C₁-C₄-alkylwherein one or more hydrogen atoms may optionally be replaced by F;

X¹, X², X³ and X⁴ which may be identical or different denote a bridgeselected from among —(CH₂)_(n)—, —(CH₂)_(n)O—, —(CH₂)_(n)—S—,—(CH₂)_(n)NR³— and —(CH₂)_(n)N⁺R³R⁴— where n=1 or 2, preferably wheren=1;

A denotes C₂-C₁₂-alkylene wherein optionally one or more hydrogen atomsmay be replaced by one or more groups selected from among F, OR³ andCOOR³, or

A denotes —(CH₂)_(l)—D—(CH₂)_(m)—, whilst in the alkylene groups—(CH₂)_(l)— and —(CH₂)_(m)— one or two hydrogen atoms may optionally bereplaced by a C₁-C₄ group and wherein

D denotes a group selected from among phenyl, cyclopentyl and cyclohexylwherein one or more hydrogen atoms may optionally be replaced by one ormore groups selected from among F, R³ and OR³ and l and m, which may beidentical or different, denote 0, 1, 2, 3 or 4, or

D denotes —O— or —NR³— and l and m, which may be identical or different,denote 2, 3 or 4;

or

A denotes —G¹—(CH₂)_(r)—G²—,

if X² or X³ represents —(CH₂)_(n)—, A also denotes —E¹—(CH₂)_(r)—G¹— or—E¹—(CH₂)_(r)—E²—,

wherein

r denotes the number 0, 1, 2, 3 or 4,

G¹ and G² which may be identical or different denote a single bond,cyclopentyl, cyclohexyl or cycloheptyl, if r=0 or r=1 G¹ and G² cannotsimultaneously represent a single bond;

E¹ and E² which may be identical or different denote a group selectedfrom among pyrrolidine, imidazolidine, piperidine and piperazine,wherein at least one N-atom is bound to X² or X³=(CH₂)_(n),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof. Of particular importance accordingto the invention are compounds of general formula (I)

wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NR^(1′)H,—CH₂NH₂, —CH₂CH₂NH₂ or —NH—C(═NH)—NH₂;

R¹ and R^(1′) which may be identical or different denote hydrogen, OH,—COR² or —COOR², preferably hydrogen or OH,

R² denotes hydrogen, C₁-C₆-alkyl or benzyl;

Ar¹, Ar², Ar³ and Ar⁴ which may be identical or different, denote phenylwhich may optionally be mono-, di— or trisubstituted by one or moregroups selected from among F, OR³, NR³R⁴, COOR₃ or C₁-C₄-alkyl, whereinin the substituent C₁-C₄-alkyl one or more hydrogen atoms may optionallybe replaced by F;

R³ and R⁴ which may be identical or different denote hydrogen or a groupselected from among cyclopropyl, cyclopentyl, cyclohexyl andC₁-C₄-alkyl, wherein one or more hydrogen atoms may optionally bereplaced by F;

X¹, X², X³ and X⁴ which may be identical or different denote a bridgeselected from among —(CH₂)_(n)—, —(CH₂)_(n)O—, —(CH₂)_(n)—S—,—(CH₂)_(n)NR³— and —(CH₂)_(n)N⁺R³R⁴— where n=1 or 2, preferably wheren=1; or

A denotes C₂-C₁₂-alkylene wherein one or more hydrogen atoms mayoptionally be replaced by one or more groups selected from among F, OR³and COOR³, or

A denotes —(CH₂)_(l)—D—(CH₂)_(m)—, whilst in the alkylene groups—(CH₂)_(l)— and —(CH₂)_(m)— one or two hydrogen atoms may optionally bereplaced by a methyl group and wherein

D denotes a group selected from among phenyl and cyclohexyl whereinoptionally one or more hydrogen atoms may be replaced by one or moregroups selected from among F, R³ and OR³ and l and m, which may beidentical or different, denote 0, 1, 2 or 3,

or

D denotes —O— and l and m, which may be identical or different, denote 2or 3;

or

A denotes —G¹—(CH₂)_(r)—G²—,

if X² or X³ represents —(CH₂)_(n)— A also denotes —E¹—(CH₂)_(r)—G¹— or—E¹—(CH₂)_(r)—E²—,

wherein

r denotes the number 0, 1, 2 or 3,

G¹ and G² which may be identical or different denote a single bond,cyclopentyl or cyclohexyl, but if r=0 or r=1 G¹ and G² cannotsimultaneously represent a single bond;

E¹ and E² which may be identical or different denote piperidine orpiperazine, wherein at least one N-atom is bound to X² or X³=(CH₂)_(n),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Also of significance according to the invention are compounds of generalformula (I),

wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NH₂,—CH₂NH₂ or —CH₂CH₂NH₂;

R¹ denotes hydrogen, OH, —COR² or —COOR², preferably hydrogen or OH,

R² denotes hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl orbenzyl;

Ar¹, Ar², Ar³ and Ar⁴, which may be identical or different, denotephenyl;

X¹, X², X³ and X⁴ which may be identical or different denote a bridgeselected from among —(CH₂)_(n)—, —(CH₂)_(n)O—, —(CH₂)_(n)NH—,—(CH₂)_(n)NMe—, —(CH₂)_(n)NEt—, —(CH₂)_(n)Nprop—,—(CH₂)_(n)Ncyclopropy—, —(CH₂)_(n)NBu— and —(CH₂)_(n)N⁺(Me)₂ where n=1;

A denotes C₂-C₁₂-alkylene which may optionally be substituted by a groupselected from among OH, COOH and COOMe, or

 —(CH₂)_(l)—D—(CH₂)_(m)—, whilst in the alkylene groups —(CH₂)_(l)— and—(CH₂)_(m)— one or two hydrogen atoms may optionally be replaced bymethyl and wherein

D denotes phenyl or cyclohexyl which may optionally be substituted bymethyl and l and m, which may be identical or different, denote 0, 1, 2or 3,

 or

D denotes —O— and l and m, which may be identical or different,represent 2 or 3;

or

A denotes —G¹—(CH₂)_(r)—G²—,

if X² or X³ denotes —(CH₂)_(n)— A may also denote —E¹—(CH₂)_(r)—G¹— or—E¹—(CH₂)_(r)—E²—,

wherein

r denotes the number 0, 1, 2 or 3,

G¹ and G² which may be identical or different denote a single bond orcyclohexyl, but if r=0 or r=1 G¹ and G² cannot simultaneously representa single bond;

E¹ and E² which may be identical or different denote piperidine orpiperazine, wherein at least one N-atom is bound to X² or X³=(CH₂)_(n),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Also preferred are compounds of general formula (IA)

wherein B1, B2, A, X² and X³ have the meanings given hereinbefore andhereinafter, optionally in the form of their racemates, enantiomers,diastereomers, tautomers and mixtures thereof, and optionally thepharmacologically harmless acid addition salts thereof.

Of particular importance are the compounds of general formula (I) or(IA) according to the invention wherein

the grouping B¹—Ar¹—X¹—Ar²—X²— denotes a group selected from among

the grouping —X³—Ar³—X⁴—Ar⁴—B² denotes a group selected from among

B¹ and B² which may be identical or different denote —C(═NR¹)—NR¹′H,—CH₂NH₂, —CH₂CH₂NH₂ or —NH—C(═NH)—NH₂;

R¹ and R¹′ which may be identical or different denote hydrogen or OH,preferably hydrogen;

A denotes a bridging group which is selected from among (viii)C₄-C₁₀-alkylene which may optionally be substituted by COOH,

 or

A may also denote

 if the grouping B¹—Ar¹—X¹—Ar²—X²— represents the group

 and the grouping —X³—Ar³—X⁴—Ar⁴—B² represents the group

 or

A may also denote

 if the grouping of the two groups B¹—Ar¹—X¹—Ar²—X²— and—X³—Ar³—X⁴—Ar⁴—B² represents the group (i) or (i′) which is bounddirectly to the piperazine-nitrogen of the group A,

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Also of special importance are the compounds of general formula (I)according to the invention wherein

the grouping B¹—Ar¹—X¹—Ar²—X²— denotes a group selected from among

the grouping —X³—Ar³—X⁴—Ar⁴—B² denotes a group selected from among

wherein

B¹ and B² which may be identical or different denote —C(═NR¹)—NR¹′H or—CH₂NH₂,

R¹ and R¹′ which may be identical or different denote hydrogen or OH,preferably hydrogen;

A denotes a bridging group which is selected from among (viii)C₄-C₁₀-alkylene,

 or

A may also denote

 if the grouping B¹—Ar¹—X¹—Ar²—X²— denotes the group (i) and thegrouping —X³—Ar³—X⁴—Ar⁴—B² denotes the group (i′),

optionally in the form of their racemates, enantiomers, diastereomers,tautomers and mixtures thereof, and optionally the pharmacologicallyharmless acid addition salts thereof.

Particularly preferred are the compounds of general formula (IA1)

wherein B¹, B², A, X² and X³ have the meanings given hereinbefore andhereinafter, optionally in the form of their racemates, enantiomers,diastereomers, tautomers and mixtures thereof, and optionally thepharmacologically harmless acid addition salts thereof.

Particularly preferred are the compounds of general formula (I), (IA) or(IA1), wherein —X²—A—X³— denotes a group of the formula

Compounds of general formula (I) wherein B¹ and B² which may beidentical or different denote —C(═NR¹)—NR^(1′)H are so-called prodrugsif neither R¹ nor R^(1′) denotes hydrogen. After being taken by thepatient these prodrugs can be converted by the body, on the basis of afunctionality which can be cleaved in vivo, into the therapeuticallyactive compounds of general formula (I) wherein B¹ and B² which may beidentical or different denote —C(═NH)NH₂.

The term alkyl groups (including those which are part of other groups)denotes branched and unbranched alkyl groups with 1 to 18 carbon atoms,preferably 1-14, most preferably 1-10 carbon atoms, unless otherwisestated. Examples include methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl and octyl, etc. Unless otherwise stated, the above terms propyl,butyl, pentyl, hexyl, heptyl and octyl, etc., also include all thepossible isomeric forms. For example, the term propyl also includes thetwo isomeric groups n-propyl and iso-propyl, the term butyl includesn-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includesiso-pentyl, neopentyl, etc. In some cases common abbreviations are alsoused to denote the abovementioned alkyl groups, such as Me for methyl,Et for ethyl etc.

Examples of alkylene groups are branched and unbranched alkylene bridgeshaving 1 to 18 carbon atoms, preferably 1-14 carbon atoms, mostpreferably 1-10 carbon atoms. These include, for example: methylene,ethylene, propylene, butylene, etc. Unless otherwise stated, the aboveterms propylene, butylene, etc. also include all the possible isomericforms. For example, the term propylene includes the two isomeric bridgesn-propylene and dimethylmethylene, the term butylene includesn-butylene, 1-methylpropylene, 2-methylpropylene, 1.1-dimethylethylene,1.2-dimethylethylene etc.

The term alkenyl groups (including those which are part of other groups)denotes branched and unbranched alkenyl groups having 2 to 16 carbonatoms, preferably 2 to 10 carbon atoms, most preferably 2 to 6 carbonatoms, if they contain at least one double bond, for example theabovementioned alkyl groups as well, provided that they contain at leastone double bond, such as for example vinyl (provided that no unstableenamines or enolethers are formed), propenyl, iso-propenyl, butenyl,pentenyl, hexenyl.

The term alkynyl groups (including those which are part of other groups)denotes branched and unbranched alkenyl groups having 2 to 16 carbonatoms, preferably 2 to 10 carbon atoms, most preferably 2 to 6 carbonatoms, provided that they have at least one triple bond, for exampleethynyl, propargyl, butynyl, pentynyl, hexynyl.

In the abovementioned alkyl groups, alkylene groups and alkenyl groups,one or more hydrogen atoms may optionally be substituted by the groupsspecified in the definitions. By the phrase “several substitutedhydrogen atoms” is meant the substitution of at least 2 hydrogen atoms.When the substituent is fluorine all the hydrogen atoms of the alkyl,alkylene and alkenyl groups may optionally be replaced.

Examples of cycloalkyl groups with 3-10 carbon atoms includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl and cyclodecyl, which may also be substituted bybranched or unbranched alkyl having 1 to 4 carbon atoms, hydroxy and/orhalogen or as hereinbefore defined.

In the abovementioned cycloalkyl groups one or more hydrogen atoms mayoptionally be substituted by the groups mentioned in the definitions. Bythe phrase “several substituted hydrogen atoms” is meant thesubstitution of at least 2 hydrogen atoms. When the substituent isfluorine all the hydrogen atoms of the cycloalkyl group may optionallybe replaced.

Fluorine, chlorine, bromine or iodine is generally referred to ashalogen.

The term C₃-C₁₀-aza-cycloalkyl groups denotes 3- to 10-memberedcycloalkyl groups which contain one or two nitrogen atoms. Theseinclude, for example, pyrrolidine, imidazolidine, piperidine,piperazine, azepan, diazepans, etc., each of which, unless otherwisespecified, may also be substituted by branched or unbranched alkyl with1 to 4 carbon atoms, hydroxy and/or halogen or as hereinbefore defined.

Examples of 5-10-membered mono- or bicyclic heteroaryl rings in which upto three carbon atoms may be replaced by one or more heteroatomsselected from among oxygen, nitrogen or sulphur include for examplefuran, thiophene, pyrrole, pyrazole, imidazole, triazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole,thiazole, thiadiazole, oxadiazole, wherein each of the abovementionedheterocycles may optionally also be condensed onto a benzene ring andwherein these heterocycles may be substituted as specified in thedefinitions.

The term C₆-C₁₀-aryl denotes an aromatic ring system with 6 to 10 carbonatoms, which, unless otherwise stated, may for example carry one or moreof the following substituents: C₁-C₆-alkyl, C₁-C₆-alkyloxy, halogen,hydroxy, mercapto, amino, alkylamino, dialkylamino, CF₃, cyano, nitro,—CHO, —COOH, —COO—C₁-C₆-alkyl, —S—C₁-C₆-alkyl. The preferred aryl groupis phenyl.

“═O” denotes an oxygen atom linked via a double bond.

In the abovementioned definitions, unless otherwise specified, all thedefinitions given for the groups —Ar¹—, —Ar²—, —Ar³— and —Ar⁴— should beregarded as two-bonded groups which may be linked to the two adjacentfunctions in three possible substitution patterns (ortho, meta andpara). Meta- and para-substitution are preferred.

In the abovementioned definitions, unless otherwise specified, all thedefinitions given for the groups —X¹—, —X²—, —A—, —X³— and —X⁴— shouldbe regarded as two-bonded groups which may be linked to the two adjacentfunctions in two possible orientations. Preferably, —X¹— denotes—O—(CH₂)_(n)—, —S—(CH₂)_(n)— or —NR³—(CH₂)_(n)— particularly —O—CH₂—;and —X⁴— denotes —(CH₂)_(n)—O—, —(CH₂)_(n)—S—or —(CH₂)—NR³—_(n),particularly —CH₂—O—.

According to another aspect, the present invention relates to the use ofthe above-defined compounds of general formula (I) as pharmaceuticalcompositions. In particular, the present invention relates to the use ofthe compounds of general formula (I) for preparing a pharmaceuticalcomposition for the prevention and/or treatment of diseases in whichtryptase inhibitors may have a therapeutic benefit.

It is preferred according to the invention to use compounds of generalformula (I) for the purpose mentioned above, for preparing apharmaceutical composition for the prevention and/or treatment ofinflammatory and/or allergic diseases.

It is particularly preferable to use the compounds of general formula(I) as mentioned above for preparing a pharmaceutical composition forthe prevention and/or treatment of bronchial asthma, allergic rhinitis,allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis,allergic gastro-intestinal disorders, Crohn's disease, ulcerativecolitis, anaphylactic shock, septic shock, shock lung (ARDS) andarthritis.

It is also advantageous to use the compounds of general formula (I) asmentioned above for preparing a pharmaceutical composition for theprevention and/or treatment of fibroses such as lung fibrosis, fibrosingalveolitis and scarring, collagenoses such as lupus erythematodes andsclerodermia as well as arteriosclerosis, psoriasis and neoplasm.

One possible method of obtaining the compounds of general formula (I)according to the invention with the aid of and using conventionalchemical methods of synthesis is diagrammatically shown hereinafter.

Method A

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² denote —C(═NH)—NH₂, imidoesters of general formula(II)

RO—C(═NH)—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—C(═NH)—OR   (II)

wherein R denotes C₁-C₆-alkyl, are reacted with ammonia.

The reaction is preferably carried out in an organic solvent attemperatures between about 0° C. and the boiling temperature of thereaction mixture, preferably between ambient temperature and about 100°C. or the boiling temperature of the solvent used, if this is lower.Suitable solvents are polar organic solvents, preferably alcohols, mostpreferably methanol, ethanol or propanols. If the starting materials aresufficiently acid-stable the reaction may take place via thecorresponding acid imide chlorides instead of via the imidoesters.

Method B1

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² denote —C(═NOH)—NH₂, compounds of general formula(III)

NC—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—CN   (III)

are treated with hydroxylamine in the presence of carbonates oralkoxides of the alkali or alkaline earth metals in solvents such asmethanol, ethanol, n-propanol or isopropanol, possibly in admixture withdioxan or tetrahydrofuran. The alkoxides may be prepared from the alkalimetals or metal hydrides and the corresponding alcohol. The reaction ispreferably carried out at 20-100° C., most preferably at the boilingtemperature of the solvent used.

Method B²

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² denote —C(═NH)—NH₂, amidoximes of general formula (I)wherein B¹ and B² denote —C(═NOH)—NH₂ are reduced.

Catalytic hydrogenation is suitable for the reduction, particularly withRaney nickel, palladium or platinum in a lower alcohol, e.g. methanol,ethanol or propanols. Appropriately the amidoxime is dissolved in apolar solvent, e.g. methanol, ethanol, propanols, tetrahydrofuran ordimethylformamide, with the addition of the calculated amount of theacid whose salt is desired as the end product, and hydrogenated atambient temperature under gentle pressure from 1 bar, e.g. at 5 bar,until the uptake of hydrogen has ceased.

Method C

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² denote —C(═NH)—NH₂, compounds of general formula (III)

NC—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—CN   (Ill)

are reacted with Li-hexamethyldisilazane. Suitable solvents for thereaction are nonpolar and polar aprotic solvents such as for exampletoluene, ether or tetrahydrofuran at temperatures of −80° C. to 120° C.To cleave the silyl groups inorganic and organic acids are used such asHCl, HBr, H₂SO₄, sulphonic acids such as p-toluenesulphonic acid,benzenesulphonic acid or methanesulphonic acid, carboxylic acids such asformic acid, acetic acid or trifluoroacetic acid at temperatures of 0°C. to 100° C.

Method D

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² may have the meanings given hereinbefore, compounds ofgeneral formula (IV and (V)

PG-B¹—Ar¹—X¹—Ar²—CHO  (IV)

OHC—Ar³—X⁴—Ar⁴—B²-PG  (V)

wherein PG may denote a protecting group suitable for protecting amines,which may also be present twice, are reacted with a diamine withsubsequent reduction of the C═N— double bonds thus formed. Suitableamino protecting groups PG which may be mentioned here include forexample alkoxycarbonyl, particularly tert-butyloxycarbonyl,benzyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl,2,2,2-trichloroethyloxycarbonyl etc. For the reaction, aldehydes offormula (IV) and (V) are reacted with diamines in aprotic solvents suchas toluene, dichloromethane, ethyl acetate, ether, tetrahydrofuran etc.at temperatures of −80° C. to 120° C. The subsequent reduction may becarried out with complex hydrides such as for example LiAlH₄,Li-alkoxyhydrides, NaBH₄, NaBHCN₃, NaBH(OAc)₃, etc.

For the reaction with primary amines NaBH₄ is preferably used, while forsecondary amines NaBH(OAc)₃ is preferred. The solvents used may be polarsolvents such as DMF, alcohols such as methanol, ethanol, propanols etc.and water. The temperature is kept in a range from −30° C. to 100° C.For cleaving the hydride complexes, organic and inorganic acids areused, such as HCl, HBr, H₂SO₄, formic acid, acetic acid, sulphonic acidssuch as p-toluenesulphonic acid, benzenesulphonic acid ormethanesulphonic acid in polar solvents such as ethyl acetate, methanol,ethanol, propanols, water, DMF, acetonitrile. Finally, the protectinggroups are cleaved, particularly with inorganic or organic acids or byhydrogenolysis or using other methods known from the prior art which areconventionally used for cleaving specific protecting groups.

Method E

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² may have the meanings given hereinbefore, compounds ofgeneral formula (VI) and (VII)

PG—B¹—Ar¹—X¹—Ar²—CH₂Y  (VI)

YCH₂—Ar³—X⁴—Ar⁴—B—PG  (VII);

wherein PG may denote a protecting group used to protect amines, whichmay also be present twice and

Y denotes fluorine, chlorine, bromine or iodine or a C₁-C₄-alkyl— or anarylsulphonate group

are reacted with a diamine or a dialcohol. Suitable amino protectinggroups PG which may be mentioned here include for examplealkoxycarbonyl, particularly tert-butyloxycarbonyl, benzyloxycarbonyl,2-trimethylsilylethyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl etc.

The reaction is carried out with basic adjuvants such as for examplealkali metal or alkaline earth metal hydroxides, alkali metal oralkaline earth metal carbonates, C₁-C₄-alkali metal alkoxides insolvents which are inert under the reaction conditions used, such asformamides—preferably dimethylformamide (DMF)—, C₁-C₄-alkyl esters ofcarboxylic acids—preferably ethyl acetate or ethyl formate—, aromatic oraliphatic hydrocarbons—preferably toluene—or in branched or unbranchedC₁-C₄-alcohols.

In the final reaction step, the protecting groups are cleaved,particularly with inorganic or organic acids or by hydrogenolysis orusing other methods known from the prior art which are conventionallyused for cleaving specific protecting groups.

Method F

In order to prepare compounds of general formula (I)

B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B   (I)

wherein B¹ and B² denote —C(═NR¹)—NH₂ with R¹≠H, compounds of generalformula (I), wherein B¹ and B² denote —C(═NH)—NH₂, are reacted withchloroformates or acyl halides or corresponding anhydrides. For this,the bis-benzamidines in solvents such as toluene, ether,dichloromethane, DMF, ethyl acetate, water at temperatures of 0° C. to120° C. are combined with acyl halides or acid anhydrides, with theaddition of a basic substance such as triethylamine, cyclic amines suchas DBU, or pyridine. The amines may also be used as solvents. Two-phasemixtures such as e.g. water/toluene or water/dichloromethane are alsosuitable for the reaction.

The compounds of formula (I) wherein B¹ and B² denote —C(═NR¹)—NH₂ (withR¹≠H) may also be prepared from the acylated amidines (IV) and (V)according to Method D and E. In this case the group R¹ acts as theprotecting group PG. There is no need here to cleave the protectinggroup PG as mentioned in Method D and E.

Method G

In order to prepare compounds of general formula (I)

 B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I)

wherein B¹ and B² denote —CH₂—NH₂, the corresponding nitrile compoundsof general formula (III)

NC—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—CN   (III)

are reduced, either by catalytic hydrogenation in solvents such asmethanol, ethanol, higher alcohols, DMF or water, with catalysts such asRaney nickel, Pd/C, platinum, or with hydride reagents, such as NaBH₄,Ca(BH₄)₂, LiAlH₄ and other Al— or B-hydrides at temperatures of 0-100°C. and pressures of 760 Torr or more.

The abovementioned methods A-G are suitable for synthesising bothsymmetrical and non-symmetrical compounds of general formula (I).

Some methods of preparing the compounds of general formula (I) accordingto the invention are described in more detail hereinafter, by way ofexample. The Examples which follow serve only as a detailedillustration, without restricting the subject of the invention.

EXAMPLE 1

(Method B1):

1.4 g of sodium carbonate and 1.83 g of hydroxylamine xHCl in 10 ml H₂Owere added dropwise to 2.3 g of the corresponding dinitrile in 80 ml ofethanol and refluxed for 3 h. The suspension formed was suction filteredand washed with ethanol. The crystals were chromatographed over silicagel 60 with acetonitrile/dichloromethane/formic acid/H₂O 70:20:15:10.After conversion into the base with 2N NaOH and extracting with ethylacetate, the substance was suspended in methanol and combined withdilute methanesulphonic acid. The solution was concentrated and slowlycrystallised with ether. 0.7 g were obtained in the form of thetrimethanesulphonate. M.p. 210-212° C.

¹H-NMR(250 MHz, DMSO-d6):δ=9.66(2H, s, OH); 7.84-7.07 (2OH, m, aryl-H);5.75 (4H, s, NH₂), 5.12 (4H, s, OCH₂—); 3.57; 3.55 (8H, 2s, N—CH₂—);2.36 (6H, s, N—CH₃); 2.11 (9H, s, CH₃—C═O).

EXAMPLE 2

(Method C):

1.74 g of the corresponding dinitrile were dissolved in 75 THF and 20 mlof lithium hexamethyldisilazane (1M) in THF were added dropwise undernitrogen. After the addition of another 25 ml of THF and heating to 45°C., the solution was stirred for 12 h at ambient temperature. 18 ml of4N hydrochloric acid were slowly added dropwise with cooling at 0° C.The THF was distilled off, water was added and the crystals were suctionfiltered and washed with water. The dihydrochloride was converted intothe base with 2N NaOH in DMF. This base was chromatographed over 160 gof silica gel 60 (acetonitrile/chloroform/glacial acetic acid/water:75:20:10:7.5).

Yield: 0.73 as the diacetate. M.p.: 221° C.

¹H-NMR(250 MHz, DMSO-d6):δ=9.92 (8H, broad, —C(═NH₂ ⁺)NH₂); 8.03-7.25(20H, m, aryl-H); 5.33 (4H, s, OCH₂—); 4.64; 4.63 (8H, 2s, —CH₂—O—CH₂—);1.74 (6H, s, CH₃—C═O).

EXAMPLE 3

(Method D):

0.49 g of diaminoethane in 2 ml dichloromethane were taken and 0.8 g of3-[4-(N-Boc-aminomethyl)-phenyloxymethyl]-benzaldehyde (70%) were added.After heating to 80° C. and cooling, 10 ml of ethanol were added and thesolution was combined with 100 mg of NaBH₄ at 0-5° C. After 12 h atambient temperature, the mixture was acidified with 1 ml of 2N HCl at0-5° C. and after 2 h the precipitated crystals were suction filtered.After dissolving in HCl/ethyl acetate, DMF and methanol, the mixture washeated and after 12 h evaporated down. The residue was taken up inmethanol and the crystals were suction filtered. Yield: 0.33 g.

¹H-NMR(250 MHz, CD₃OD):δ=7.75-7.10 (16H, m, aryl-H); 5.19 (4H, s,OCH₂—); 4.32(4H, s, N—CH₂-phenyl); 4.09 (4H, s, CH₂NH₂); 3.47 (4H, s,N—CH₂CH₂—N).

EXAMPLE 4

(Method E):

3.75 g of N-Boc-2-[4-(3-chlormethyl-benzyloxy-)phenyl]ethylamine, 0.72 gof 2,5-diamino-2,5-dimethyl-hexane, 1.4 g of potassium carbonate and 0.1g of potassium iodide in 15 ml of DMF were stirred for 6 h at aninternal temperature of 75° C. and for a further 7 h at 140° C. Thesuspension was evaporated down, the residue was taken up in water andextracted with ethyl acetate. The organic phase dried over Na₂SO₄ wasevaporated down and the residue was chromatographed over silica gel 60with dichloromethane/methanol/conc. ammonia 65:35:5. The Boc-protectedcompound was dissolved in 10 ml of ethyl acetate and mixed with 10 ml of3M HCl in ethyl acetate and stirred for 24 h. The crystals precipitatedwere recrystallised from 50 ml of ethanol. Yield: 0.22 g in the form ofthe tetrahydrochloride. M.p.: 270° C. (decomposition).

¹H-NMR(250 MHz, CD₃OD):δ=7.85-6.98 (16H, m, aryl-H); 5.16 (4H, s,OCH₂—); 4.30 (4H, s, N—CH₂-phenyl); 3.15; 2.90 (8H, 2m,N—CH₂—CH₂-phenyl); 1.95 (4H, s, C—CH₂CH₂—); 1.52 (12H, s, CH₃—C—CH₃).

EXAMPLE 5

(Method F):

0.3 g of the corresponding bis-benzamidine were dissolved as the base ina little absolute ethanol. 50 ml of dichloromethane and 0.115 g of ethylchloroformate were added thereto and at ambient temperature 1 ml oftriethylamine was added dropwise. After 2 h the mixture was extractedtwice with 50 ml of water. The organic phases were evaporated down andchromatographed over silica gel 60 (acetonitrile/dichloromethane/formicacid/H₂O 70:20:15:10). The product was taken up in water, combined withsodium hydroxide solution, extracted with 100 ml of ethyl acetate, driedand evaporated down.

Yield: 85 mg in the form of a colourless oil.

¹H-NMR(250 MHz, CDCl₃):δ=8.50 (4H, s, NH₂); 8.02-6.96 (16H, m, aryl-H);5.18 (4H, s, OCH₂—); 4.25 (4H, qu, J=7.0 HZ, OCH₂—CH₃); 4.10 (4H, s,N—CH₂-phenyl); 2.80-1.07 (12H, m, N—CH₂(CH₂)₄—CH₂—N); 2.55 (6H, s,N—CH₃); 1.28 (6H, t, J=7.0 HZ, OCH₂—CH₃).

EXAMPLE 6

(Method G):

1.16 g of the corresponding dinitrile in 60 ml DMF were hydrogenatedwith the addition of methanolic ammonia solution and Raney nickel for 6h at 5 bar and 60° C. The catalyst was removed by suction filtering andthe solvent was eliminated. The residue was dissolved while hot in 100ml of DMF and after cooling down the solution was suction filtered. Thefiltrate was dissolved in 50 ml of DMF, the calculated amount ofethereal hydrochloric acid was added, the solvent was distilled off andstirred with ethanol. The residue was converted into the base usingconc. ammonia and chromatographed over 70 g of silica gel 60(acetonitrile/chloroform/glacial acetic acid/water 75:20:10:7.5).

Yield: 0.24 g in the form of the diacetate. M.p.: 148° C.

¹H-NMR(250 MHz, DMS0-d6):δ=7.44-6.86 (2OH, m, aryl-H); 5.08 (4H—OCH₂—);4.60 (6H, s, CH₃); 4.52; 4.51 (8H, 2s, —CH₂—O—CH₂—); 3.69 (4H, s,CH₂—NH₂); 1.81 (6H, s, CH₃—C═O).

The following compounds, inter alia, were also obtained analogously tothe examples of synthesis described above and according to synthesismethods A-G:

EXAMPLE 7

(Method G):

¹H-NMR(250 MHz, CD₃OD):δ=7.72-7.07 (16H, m, aryl-H); 5.20 (4H, s, OCH₂);4.25 (4H, s, N—CH₂-phenyl); 4.10 (4H, s, CH₂—NH₂); 3.09 (4H, m,N—CH₂(CH₂)₃—CH₂—N); 1.89-1.40 (6H, m, N—CH₂(CH₂)—).

EXAMPLE 8

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.62-7.02 (16H, m, aryl-H); 5.14 (4H, s,OCH₂—); 4.20 (4H, s, H—CH₂-phenyl); 4.06 (4H, s, CH₂—NH₂); 2.99 (4H, m,N—CH₂—(CH₂)₁₀—CH₂—N); 1.82-1.17 (20H, m, N—(CH₂)₁₀—).

EXAMPLE 9

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.93-7.19 (16H, m, aryl-H); 5.28 (4H, s,OCH₂—); 4.33 (4H, s, N—CH₂-phenyl); 4.13 (4H, s, CH₂—NH₂); 2.03-1.38(8H, m, C—(CH₂)₄—C); 1.48 (12H, s, C—(CH₃)₂).

EXAMPLE 10

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.63-6.85 (20H, m, aryl-H); 5.10; 5.04(4H, 2s,OCH₂); 4.40; 4.18; 4.01 (8H, 3s, N—CH₂); 3.20; 2.95 (4H, 2m,H—CH₂CH₂—N).

EXAMPLE 11

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.70-7.03 (16H, m, aryl-H); 5.15 (4H, s,OCH₂—); 4.20 (4H, s, N—CH₂-phenyl); 4.05 (4H, s, CH₂—NH₂); 2.82 (4H, d,J=5.8 Hz, CH₂—CH); 2.00-0.95 (10H, m, cyclohexyl-H).

EXAMPLE 12

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.76-7.07 (16H, m, aryl-H); 5.19 (4H, s, OCH₂);4.37 (1H, m, CH-OH); 4.29 (4H, s, N—CH₂-phenyl); 4.09 (4H, s, CH₂—MH₂);3.16 (4H, m, —CH ₂—CHOH—CH ₂—).

EXAMPLE 13

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.70-7.05 (16H, m, aryl-H); 5.15 (4H, s, OCH₂);4.23 (4H, s, N—CH₂-phenyl); 4.07 (4H, s, CH₂—NH₂); 3.02 (4H, S,—CH₂—C—CH₂—); 1.11 (6H, s, CH₃—C—CH₃).

EXAMPLE 14

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.88-7.17 (16H, m, aryl-H); 5.27 (4H, s, OCH₂);4.31 (4H, s, N—CH₂-phenyl); 4.13 (4H, s, CH₂—NH₂); 1.93 (4H, s,C—CH₂CH₂—C); 1.51 (12H, s, CH₃—C—CH₃).

EXAMPLE 15

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.79-7.13 (2OH, m, aryl-H; 5.22 (4H, s, OCH₂);4.28 (8H, s, N—CH₂-phenyl); 4.11 (4H, s, CH₂—NH₂).

EXAMPLE 16

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.60-7.00 (2OH, m, aryl-H); 5.14 (4H, s, OCH₂);4.15 (8H, s, N—CH₂-phenyl); 4.04 (4H, s, NH₂—CH₂).

EXAMPLE 17

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=9.54 (4H, s, NH₂ ⁺); 9.23; 9.09 (8H, 2s,—C(═NH₂ ⁺)NH₂); 7.90-7.15 (16H, m, aryl-H); 5.22 (4H, s, OCH₂); 4.11(4H, N—CH₂-phenyl); 2.83 (4H, m, N—CH₂(CH₂)₃—CH₂—N); 1.54-0.90 (6H, m,N—CH₂—(CH₂—).

EXAMPLE 18

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.89-7.20(16H, m, aryl-H); 5.28 (4H, s, OCH₂);4.39; 4.33 (4H, 2s, N—CH₂-phenyl); 4.15 (4H, s, CH₂—NH₂); 2.43-1.30 (9H,m, cyclohexyl); 1.56 (3H, s, C—CH₃); 1.50 (6H, s, CH₃—C—CH₃).

EXAMPLE 19

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.68-6.93 (16H, m, aryl-H); 5.08 (4H, s, OCH₂);4.19 (4H, s, N—CH₂-phenyl); 4.02 (4H, s, CH₂—NH₂); 3.08 (2H, m,N—CH-cyclohexyl); 2.30-0.88 (20H, cyclohex-CH₂-cyclohex-H).

EXAMPLE 20

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.85-7.13 (16H, m, aryl-H); 5.23 (4H, s, OCH₂);4.31 (4H, s, N—CH₂-phenyl); 4.11 (4H, s, CH₂—NH₂); 3.12 (4H, m,N—CH₂-cyclohexyl); 2.33-0.73 (10H, m, cyclohexyl-H).

EXAMPLE 21

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.93-7.15 (16H, m, aryl-H); 5.28 (4H, s, OCH₂);4.35 (4H, s, N—CH₂-phenyl); 4.14 (4H, m, CH₂—NH₂); 3.76-3.46 (12H, m,NCH₂CH₂-pip.).

EXAMPLE 22

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=9.54 (4H, s, NH₂); 9.23; 9.09 (8H, 2s,C(═NH₂NH₂ ⁺)NH₂); 7.90-7.15 (16H, m, aryl-H); 5.22 (4H, s, OCH₂); 4.11(4H, N—CH₂-phenyl); 2.83 (4H, m, N—CH₂(CH₂)₃—CH₂—N); 1.54-0.90 (6H, m,N—CH₂—(CH₂)₃—).

EXAMPLE 23

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.88-7.16 (16H, m, aryl-H); 5.27 (4H, s, OCH₂);4.24 (4H, s, N—CH₂-phenyl); 3.05 (4H, m, N—CH₂—(CH₂)₅—CH₂—N—); 1.89-1.27(1OH, m, N—CH₂(CH₂)₅—).

EXAMPLE 24

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.85-7.15 (16H, m, aryl-H); 5.27 (4H, s,OCH₂—); 4.51; 4.29 (4H, m, N—CH₂-phenyl); 3.20 (4H, m,N—CH₂—(CH₂)₄—CH₂—N); 2.81 (6H, s, N—CH₃); 2.03-1.35 (8H, m,N—CH₂—(CH₂)₄—).

EXAMPLE 25

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.98-7.26 (16H, m, aryl-H); 5.32 (4H, s,OCH₂—); 4.28 (4H, s, N—CH₂-phenyl); 3.08 (4H, m, N—CH₂—(CH₂)₄—CH₂-N);1.89-1.32 (8H, m, N—CH₂—(CH₂)₄—).

EXAMPLE 26

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.80-7.13 (16H, m, aryl-H); 5.22 (4H, s, OCH₂);4.22 (4H, s, N—CH₂-phenyl); 2.90 (4H, d, J=7.4 Hz, N—CH₂-cyclohexyl);2.13-0.93 (10H, m, cyclohexyl-H).

EXAMPLE 27

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=10.15; 9.20; 8.37 (12H, 3s, NH₂); 7.99-7.11(16H, m, aryl-H); 5.22 (4H, s, OCH₂—); 4.00 (4H, s, N—CH₂-phenyl);1.91-1.12 (4H, m, —C—CH₂CH₂—C); 1.30 (12H, s,—C(CH₃)₂—CH₂—CH₂—C(CH₃)₂—).

EXAMPLE 28

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=8.03-7.23 (20H, m, aryl-H); 5.33 (4H, s, OCH₂);4.31 (8H, s, N—CH₂-phenyl).

EXAMPLE 29

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=8.03-7.29 (2OH, m, aryl-H); 5.37 (4H, s, OCH₂);4.40 (8H, s, N—CH₂-phenyl).

EXAMPLE 30

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.96-7.19 (16H, m, aryl-H); 5.32 (4H, s,OCH₂—); 4.43; 4.41 (4H, m, N—CH₂-phenyl); 3.15 (8H, m,N—CH₂—(CH₂—)₄—CH₂—N; N—CH₂—CH₂CH₃); 2.03-1.22 (16H, m, N—CH₂—(CH₂)₄;N—CH₂CH₂CH₂CH₃); 0.95 (6H, m, N—(CH₂)₃—CH₃).

EXAMPLE 31

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.74-7.00 (16H, m, aryl-H); 5.17 (4H, s,OCH₂—); 4.40 (4H, s, N—CH₂-phenyl); 4.05 (4H, s, CH₂—NH₂); 3.18 (4H, m,N—CH₂(CH₂)₄—CH₂—N); 2.77 (6H, s, N—CH₃); 1.95-1.36 (8H, m, N—CH₂(CH₂)₄).

EXAMPLE 32

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.91-7.10 (16H, m, aryl-H); 5.23 (4H, s,OCH₂—); 4.24 (4H, s, N—CH₂-phenyl); 2.86 (3H, m, NH—CH—; N—CH₂—CH₂CH₂);2.05-1.24 (6H, m, N—CH₂—CH₂CH₂).

EXAMPLE 33

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=9.61; 9.56; 9.38 (12H, 3, s, NH₂; C(═NH₂⁺)NH₂); 8.22-7.43 (16H, m, aryl-H); 5.34 (4H, s, OCH₂—); 4.28 (4H, s,N—CH₂-phenyl); 2.05-1.27 (8H, m, C—CH₂CH₂—CH₂CH₂—C); 1.49 (12H, S,CH₃—C—CH₃).

EXAMPLE 34

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.80-7.06 (16H, m, aryl-H); 5.18 (4H, s,OCH₂—); 3.48 (4H, s, N—CH₂-phenyl); 2.97-0.92 (18H, m, pip-H).

EXAMPLE 35

(Method E):

¹H-NMR(250 MHz, CD₃OD):δ=7.88-7.02 (2OH, m, aryl-H); 5.21 (4H, s,OCH₂—); 4.55; 4.43 (8H, 2s, N—CH₂-phenyl); 3.16; 2.93 (8H, 2m,N—CH₂CH₂-phenyl); 2.75 (6H, s, N—CH₃).

EXAMPLE 36

(Method B1):

¹H-NMR(250 MHz, DMSO-d6):δ=13.16 (2H, s, C═N—OH); 11.33 (4H, s, NH₂);10.26 (4H, s, NH₂); 7.86-7.22 (20H, m, aryl-H); 5.31 (4H, s, OCH₂—);4.21 (8H, s, N—CH₂-phenyl).

EXAMPLE 37

(Method F):

¹H-NMR(250 MHz, DMSO-d6):δ=9.14 (8H, s, NH₂); 8.11-7.04 (16H, m,aryl-H); 5.19 (4H, s, OCH₂—); 4.11 (4H, s, N—CH₂-phenyl); 3.59 (6H, s,OCH₃); 1.60-1.15 (8H, m, C—(CH₂)₄; 1.31 (18H, s, CH₂—C—CH₃).

EXAMPLE 38

(Method G):

¹H-NMR(250 MHz, CD₃OD):δ=7.76-7.06 (20H, m, aryl-H); 5.19 (4H, s,OCH₂—); 4.51; 4.38 (8H, 2s, N—CH₂-phenyl); 4.05 (4H, s, CH₂—NH₂); 2.72(6H, s, N—CH₃).

EXAMPLE 39

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=9.80; 9.42; 9.19 (12H, 3s, NH₂ ⁺, C(═NH₂⁺)NH₂); 7.97-7.13 (16H, m, aryl-H); 5.22 (4H, s, OCH₂—); 4.20 (4H, s,N—CH₂-phenyl); 3.75; 3.06 (8H, 2m, N—CH₂—CH₂—O).

EXAMPLE 40

(Method D):

¹H-NMR(250 MHz, DMSO-d6):δ=9.31; 9.11; 9.09 (12H, 3s, NH₂ ⁺, C(═NH₂⁺)NH₂); 8.00-7.15 (16H, m, aryl-H); 5.23 (4H, s, OCH₂); 4.11 (4H, s,N—CH₂-phenyl); 2.37-0.83 (9H, m, pip-H); 1.38 (6H, s, C(CH₃)₂); 1.29(3H, s, C—CH₃).

EXAMPLE 41

(Method D):

¹H-NMR(250 MHz, CD₃OD):δ=7.80-7.06 (16H, m, aryl-H); 5.18 (4H, s,OCH₂—); 3.48 (4H, s, N—CH₂-phenyl); 2.97-0.92 (18H, m, pip-H).

EXAMPLE 42

(Method E):

¹H-NMR(250 MHz, CD₃OD):δ=7.43-6.85 (16H, m, aryl-H); 5.15 (4H, s, OCH₂);3.49 (4H, s, N—CH₂-phenyl); 2.88-0.93 (26H, m, CH₂—CH₂—NH₂; pip.-H).

EXAMPLE 43

(Method D):

EXAMPLE 44

(Method D):

EXAMPLE 45

(Method D):

EXAMPLE 46

(Method E):

EXAMPLE 47

(Method D):

EXAMPLE 48

(Method D):

EXAMPLE 49

(Method D):

EXAMPLE 50

(Method D):

EXAMPLE 51

(Method D):

EXAMPLE 52

(Method D):

EXAMPLE 53

(Method B1):

EXAMPLE 54

(Method G):

EXAMPLE 55

(Method F):

EXAMPLE 56

(Method B1/B2):

EXAMPLE 57

(Method F):

EXAMPLE 58

(Method F):

EXAMPLE 59

(Method F):

EXAMPLE 60

(Method F):

EXAMPLE 61

(Method F):

EXAMPLE 62

(Method D):

EXAMPLE 63

(Method D):

EXAMPLE 64

(Method D):

EXAMPLE 65

(Method D):

EXAMPLE 66

(Method B1):

EXAMPLE 67

(Method B1):

EXAMPLE 68

(Method G):

The compounds according to the invention are characterised by theirtryptase-inhibiting activity. This ability to inhibit tryptase wasinvestigated using the test described below.

The measurement is carried out in Tris HCl buffer (100 mM), whichadditionally contains calcium (5 mM) and heparin (100 mg/ml), at pH 7.4.The standard used is rh beta tryptase which may be obtained commerciallyfrom Promega, for example. The substrate used isN-p-tosyl—Gly-Pro-Lys-para-nitroaniline in a concentration of 0.6 mM.The substrate is digested with tryptase to form p-nitroaniline which canbe measured at 405 nm. Usually, an incubation period of 5 minutes and anincubation temperature of 37° C. are chosen. The enzyme activity used is0.91 U/ml. The measurements are carried out in an Autoanalyser (CobasBio) made by Hofmann LaRoche. The potential inhibitory substances areused in concentrations of 10 μM in the screening, the inhibition of thetryptase being given in percent. The IC₅₀ (concentration at which 50% ofthe enzyme activity is inhibited) is determined at over 70% inhibition.After 5 minutes' pre-incubation of the potential inhibitory substances,the substrate is added to start the reaction, the formation ofp-nitroaniline being taken as a measurement of the enzyme activity after5 minutes, after testing the linearity.

The IC50 values obtained for the compounds according to the inventionare shown in Table 1.

TABLE 1 Example salt form IC₅₀ value [nM] 2 diacetate 19 7 tetrachloride4.3 10 tetrachloride 35 11 tetrachloride 4 14 tetrachloride 13 15tetrachloride 23 16 tetrachloride 12 17 tetrachloride 1.4 18tetrachloride 10.7 19 tetrachloride 10 20 tetrachloride 7.1 22tetrachloride 27.4 23 tetrachloride 1.1 24 tetrachloride 3.1 25tetrachloride 1.2 26 tetrachloride 0.8 27 tetrachloride 1.7 28tetrachloride 5.3 29 tetrachloride 1.7 30 tetrachloride 6.8 31tetrachloride 13 32 tetrachloride 32.4 33 tetrachloride 2.5 34tetrachloride 0.8 35 tetrachloride 31.6 39 tetrachloride 12 40tetrachloride 5 41 tetrachloride 4.6 42 tetrachloride 30.9 56 diacetate19 62 tetrachloride 41 63 tetrachloride 0.74 64 tetrachloride 1.1 65tetrachloride 0.59 68 tetrachloride 2.5

The trytase inhibitors according to the invention may be administredorally, transdermally, by inhalation or parenterally. The compoundsaccording to the invention occur as active ingredients in conventionalpreparations, for example in compositions which consist essentially ofan inert pharmaceutical carrier and an effective dose of the activesubstance, such as for example tablets, coated tablets, capsules,powders, solutions, suspensions, emulsions, syrups, suppositories,transdermal systems, etc. An effective dose of the compounds accordingto the invention is between 1 and 100, preferably between 1 and 50, mostpreferably between 5-30 mg/dose for oral administration, and between0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous orintramuscular administration. For inhalation, according to theinvention, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5%active substance are suitable. For administration by inhalation the useof powders is preferred. It is also possible to use the compoundsaccording to the invention as a solution for infusion, preferably in aphysiological saline or nutrient saline solution.

The compounds according to the invention may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions, elixirs, emulsions or dispersible powders.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanilline or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

A therapeutically effective daily dose is between 1 and 800 mg,preferably 10-300 mg per adult.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg corn starch 190 mg  lactose55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Coated tablets per coated tablet Active substance  5 mg Corn starch41.5 mg   Lactose 30 mg Polyvinylpyrrolidone  3 mg Magnesium stearate0.5 mg  80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine . The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax.

D) Capsules per capsule Active substance 50 mg Corn starch 268.5 mg  Magnesium stearate 1.5 mg  320 mg 

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

F) Suppositories Active substance  50 mg Solid fat 1650 mg 1700 mg

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

What is claimed is:
 1. A compound of formula (I)B¹—Ar¹—X¹—Ar²—X²—A—X³—Ar³—X⁴—Ar⁴—B²   (I) wherein: B¹ and B², which areidentical or different, are each —C(═NR¹)—NR^(1′)H, —CH₂NH₂, —CH₂CH₂NH₂,or —NH—C(═NH)—NH₂; R¹ and R^(1′), which are identical or different, areeach hydrogen, OH, —COR², or —COOR²; R² is hydrogen, C₁-C₁₈-alkyl, Ar⁵,or Ar⁵—C₁-C₆-alkyl; Ar¹, Ar², Ar³, and Ar⁴, which are identical ordifferent, are each C₆-C₁₀-aryl- which is optionally mono- totetrasubstituted by one or more groups selected from C₃-C₁₀-cycloalkyl,F, Cl, Br, I, OH, OR³, SR³, NR³R⁴, COOR³, C₁-C₆-alkyl, C₂-C₆-alkenylC₂-C₆-alkynyl, wherein in the substituents C₁-C₆-alkyl andC₂-C₆-alkenyl, one or more hydrogen atoms are optionally replaced by For OR³; Ar⁵ is C₆-C₁₀-aryl- which is optionally mono- totetrasubstituted by one or more groups selected from C₃-C₁₀-cycloalkyl,F, Cl, Br, I, OH, OR³, SR³, NR³R⁴, COR³, C₁-C₆-alkyl, C₂-C₆-alkenyl, andC₂-C₆-alkynyl, wherein in the substituents C₁-C₆-alkyl andC₂-C₆-alkenyl, one or more hydrogen atoms are optionally replaced by For OR³, or  a 5-10-membered mono- or bicyclic heteroaryl ring, whereinup to three carbon atoms are replaced by one or more heteroatomsselected from oxygen, nitrogen, and sulfur and which are optionallymono- to tetrasubstituted by one or more groups selected fromC₁-C₁₀-cycloalkyl, F, Cl, Br, I, OH, OR³, SR³, NR³R⁴, COOR³,C₁-C₆-alkyl, C₂-C₆-alkenyl, and C₂-C₆-alkynyl, wherein in thesubstituents C₁-C₆-alkyl and C₂-C₆-alkenyl, one or more hydrogen atomsare optionally replaced by F or OR³; R³ and R⁴, which are identical ordifferent, are each hydrogen or a group selected from C₁-C₆-alkyl andC₃-C₆-cycloalkyl, wherein one or more hydrogen atoms are optionallyreplaced by F; X¹ and X⁴, which are identical or different, are each—(CH₂)_(n)O—or —(CH₂)_(n)—S—; X² and X³, which are identical ordifferent, are each —(CH₂)_(n)—; n is 1 or 2 in each case; A is—E¹—(CH₂)_(r)—E²—, wherein r is 0, 1, 2, 3, 4, 5, or 6, and E¹ and E²are each piperidine or piperazine, or a tautomer or pharmaceuticallyacceptable salt thereof.
 2. The compound of formula (I) according toclaim 1, wherein: R² is hydrogen, C₁-C₁₄-alkyl, Ar⁵, or Ar⁵—C₁-C₆-alkyl;Ar¹, Ar², Ar³, and Ar⁴, which are identical or different, are eachC₆-C₁₀-aryl- which are optionally mono- to tetrasubstituted by one ormore groups selected from C₃-C₈-cycloalkyl, F, Cl, Br, I, OH, OR³,NR³R⁴, COOR₃, C₁-C₆-alkyl, C₂-C₆-alkenyl, and C₂-C₆-alkynyl, wherein inthe substituents C₁-C₆-alkyl and C₂-C₆-alkenyl, one or more hydrogenatoms are optionally replaced by F; and Ar⁵ is C₆-C₁₀-aryl- which isoptionally mono- to tetrasubstituted by one or more groups selected fromC₃-C₈-cycloalkyl, F, Cl, Br, I, OH, OR³, NR³R⁴, COOR₃, C₁-C₆-alkyl,C₂-C₆-alkenyl, and C₂-C₆-alkynyl, wherein in the substituentsC₁-C₆-alkyl and C₂-C₆-alkenyl, one or more hydrogen atoms are optionallyreplaced by F, or  a 5-10-membered mono- or bicyclic heteroaryl ring,wherein up to three carbon atoms are replaced by one or more heteroatomsselected from oxygen, nitrogen, and sulfur and which are optionallymono- to tetrasubstituted by one or more groups selected from F, OR³,COOR³, or C₁-C₆-alkyl, wherein in the substituent C₁-C₆-alkyl, one ormore hydrogen atoms are optionally replaced by F, or a tautomer orpharmaceutically acceptable salt thereof.
 3. The compound of formula (I)according to claim 1, wherein: R² is hydrogen, C₁-C₁₀-alkyl, orAr⁵—C₁-C₄-alkyl; Ar¹, Ar², Ar³, Ar⁴, and Ar⁵, which are identical ordifferent, are each phenyl or naphthyl which are optionally mono-, di-,or trisubstituted by one or more groups selected from F, OR³, NR³R⁴,COOR₃, or C₁-C₆-alkyl, wherein in the substituent C₁-C₆-alkyl, one ormore hydrogen atoms are optionally replaced by F or OR³; R³ and R⁴,which are identical or different, are each hydrogen or a group selectedfrom cyclopropyl, cyclopentyl, cyclohexyl, and C₁-C₄-alkyl, wherein oneor more hydrogen atoms are optionally replaced by F; and r is 0, 1, 2,3, or 4, or a tautomer or pharmaceutically acceptable salt thereof. 4.The compound of formula (I) according to claim 1, wherein: R² ishydrogen, C₁-C₆-alkyl, or benzyl; Ar¹, Ar², Ar³, and Ar⁴, which areidentical or different, are each phenyl which are optionally mono-, di-,or trisubstituted by one or more groups selected from F, OR³, NR³R⁴,COOR₃, or C₁-C₄-alkyl, wherein in the substituent C₁-C₄-alkyl, one ormore hydrogen atoms are optionally replaced by F; R³ and R⁴, which areidentical or different, are each hydrogen or a group selected fromcyclopropyl, cyclopentyl, cyclohexyl, and C₁-C₄-alkyl, wherein one ormore hydrogen atoms are optionally replaced by F; and r is 0, 1, 2, or3, or a tautomer or pharmaceutically acceptable salt thereof.
 5. Thecompound of formula (I) according to claim 1, wherein: B¹ and B², whichare identical or different, are each —C(═NR¹)—NH₂, —CH₂NH₂, or—CH₂CH₂NH₂; R² is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl,or benzyl; Ar¹, Ar², Ar³, and Ar⁴ are each phenyl; n is 1; and r is 0,1,2 or 3, or a tautomer or pharmaceutically acceptable salt thereof. 6.The compound of formula (I) according to claim 1, wherein n is
 1. 7. Thecompound of formula (I) according to claim 1, wherein: X¹ is —O—(CH₂)—;and X⁴ is —(CH₂)—O—.
 8. A compound of formula (IA)

wherein: B¹ and B², which are identical or different, are each—C(═NR¹)—NR^(1′)H, —CH₂NH₂, —CH₂CH₂NH₂, or —NH—C(═NH)—NH₂; R¹ andR^(1′), which are identical or different, are each hydrogen, OH, —COR²,or —COOR²; R² is hydrogen, C₁-C₁₈-alkyl, aryl, or aryl-C₁-C₆-alkyl; X²and X³, which are identical or different, are each —(CH₂)_(n)—, where nis 1 or 2; and A is —E¹—(CH₂)_(r)—E²—, wherein r is 0, 1, 2, 3, 4, 5, or6, and E¹ and E² are each piperidine or piperazine, or a tautomer orpharmaceutically acceptable salt thereof.
 9. The compound of the formula(IA) according to claim 8, wherein R² is hydrogen, C₁-C₁₄-alkyl, aryl,or aryl-C₁-C₆-alkyl, or a tautomer or pharmaceutically acceptable saltthereof.
 10. The compound of formula (IA) according to claim 9, whereinR² is hydrogen, C₁-C₁₀-alkyl, or aryl-C₁-C₆-alkyl, or a tautomer orpharmaceutically acceptable salt thereof.
 11. The compound of formula(IA) according to claim 8, wherein R² is hydrogen, C₁-C₆-alkyl, orbenzyl, or a tautomer or pharmaceutically acceptable salt thereof. 12.The compound of formula (IA) according to claim 8, wherein: B¹ and B²,which are identical or different, are each —C(═NR¹)—NH₂, —CH₂NH₂, or—CH₂CH₂NH₂; R² is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl,or benzyl; and n is 1, or a tautomer or pharmaceutically acceptable saltthereof.
 13. The compound of formula (I) according to claim 1, wherein:the grouping B¹—Ar¹—X¹—Ar²—X²— is a group selected from:

the grouping —X³—Ar³—X⁴—Ar⁴—B² is a group selected from:

wherein: B¹ and B², which are identical or different, are each—C(═NR¹)—NR^(1′)H, —CH₂NH₂, —CH₂CH₂NH₂, or —NH—C(═NH)—NH₂; R¹ andR^(1′), which are identical or different, are each hydrogen or OH;

or a tautomer or pharmaceutically acceptable salt thereof.
 14. Acompound of formula (I) according to claim 1, wherein: the groupingB¹—Ar¹—X¹—Ar²—X²— is a group selected from:

the grouping —X³—Ar³—X⁴—Ar⁴—B² is a group selected from:

wherein B¹ and B², which are identical or different, are each—C(═NR¹)—NR^(1′)H or —CH₂NH₂, R¹ and R^(1′), which are identical ordifferent, are each hydrogen or OH,

or a tautomer or pharmaceutically acceptable salt thereof.
 15. Acompound of formula (IA1)

wherein: B¹ and B², which are identical or different, are each—C(═NR¹)—NR^(1′)H, —CH₂NH₂, —CH₂CH₂NH₂, or —NH—C(═NH)—NH₂; R¹ andR^(1′), which are identical or different, are each hydrogen, OH, —COR²,or —COOR²; R² is hydrogen, C₁-C₁₈-alkyl, aryl, or aryl-C₁-C₆-alkyl; X²and X³, which are identical or different, are each —(CH₂)_(n)—, where nis 1 or 2; and A is —E¹—(CH₂)_(r)—E²—, wherein r is 0, 1, 2, 3, 4, 5, or6, and E¹ and E² are each piperidine or piperazine, or a tautomer orpharmaceutically acceptable salt thereof.
 16. The compound of formula(IA1) according to claim 15, wherein R² is hydrogen, C₁-C₁₄-alkyl, aryl,or aryl-C₁-C₆-alkyl, or a tautomer or pharmaceutically acceptable saltthereof.
 17. A compound of formula (IA1) according to claim 15, wherein:R² is hydrogen, C₁-C₁₀-alkyl, or aryl-C₁-C₄-alkyl; and r is 0, 1, 2, 3,or 4, or a tautomer or pharmaceutically acceptable salt thereof.
 18. Thecompound of formula (IA1) according to claim 15, wherein: R² ishydrogen, C₁-C₆-alkyl, or benzyl; and r is 0, 1, 2, or 3, or a tautomeror pharmaceutically acceptable salt thereof.
 19. The compound of formula(IA1) according to claim 15, wherein: B¹ and B², which are identical ordifferent, are each —C(═NR¹)—NH₂, —CH₂NH₂, or —CH₂CH₂NH₂; R² ishydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, or benzyl; n is1; and r is 0, 1, 2, or 3, or a tautomer or pharmaceutically acceptablesalt thereof.
 20. A compound of formula (I) according to claim 1,wherein A is

or a tautomer or pharmaceutically acceptable salt thereof.
 21. Thecompound of formula (I) according to claim 1, wherein —X²—A—

or a tautomer or pharmaceutically acceptable salt thereof.
 22. Acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 23. A method for treatingan inflammatory or allergic disease condition which comprisesadministering to a host suffering from such condition, a therapeuticamount of the compound of formula (I) according to claim 1, the compoundof formula (IA) according to claim 8, or the compound of formula (IA1)according to claim
 15. 24. The method of claim 23, wherein the diseasecondition is selected from the group consisting of: bronchial asthma,allergic rhinitis, allergic conjunctivitis, atopic dermatitis,urticaria, allergic otitis, allergic gastrointestinal disorders, Crohn'sdisease, ulcerative colitis, anaphylactic shock, septic shock, shocklung (ARDS), and arthritis.
 25. The method of claim 23, wherein thedisease condition is selected from the group consisting of: fibrosesfibrosing alveolitis and scarring, collagenoses, scleroderma,arteriosclerosis, and psoriasis.
 26. A pharmaceutical compositioncomprising: (a) the compound of formula (I) according to claim 1, thecompound of formula (IA) according to claim 8, or the compound offormula (IA1) according to claim 15; and (b) a pharmaceuticallyacceptable carrier.